Lysosomal storage disorders represent a group of more than forty rare and inherited metabolic disorders caused by the deficiency or inactivity of specific lysosomal enzymes. In particular, lysosomal storage disorders are caused by the deficiency or inactivity of the lysosomal enzymes which catalyze the stepwise metabolism of lipids or complex glycoproteins known as glycosaminoglycans. As a result of this metabolic deficiency, metabolic precursors progressively accumulate in the cells, tissues and, in particular, the cellular lysosomes of affected subjects. This protein accumulation causes a permanent, progressive cellular damage which affects the appearance, physical abilities, organ and system functioning and, in most cases, the mental development of affected subjects. Although the enzyme deficiencies affect every tissue, a patient's clinical expression may frequently vary depending, for example, on the degree of enzyme deficiency or impairment. The lysosomal storage disorder may also be associated with some degree of neuronal cell loss, predominantly resulting in neurological symptoms, including, mental retardation, severe motor impairments, physical disability, a decreased lifespan and/or combinations of the foregoing.
There are no cures for the lysosomal storage disorders, and treatment is often palliative, offered to subjects primarily to improve their quality of life. Enzyme replacement therapy (ERT) has been a useful therapeutic option for subjects with lysosome storage disorders. ERT generally involves the parenteral administration of natural or recombinantly-derived proteins and/or enzymes to a patient. Approved therapies are administered to patients intravenously and are generally effective in treating the somatic or peripheral symptoms of the underlying enzyme deficiency. To effectively treat lysosomal storage disorders, the administered therapeutic agent (e.g., the deficient lysosomal enzyme) must distribute into the affected cells and tissues after being infused into a patient's bloodstream.
To achieve distribution of the requisite enzymes into affected cells and tissues, the enzymes are generally targeted to specific cell-surface receptors that transport the enzymes into the cells through receptor-mediated endocytosis. For example, in Gaucher's disease, the deficient enzyme, glucocerebrosidase, is targeted to the appropriate cells through the binding of exposed mannose residues on the enzyme to the mannose receptor, which is abundantly expressed on target cells (reticuloendotheilial cells). In cells that lack the mannose receptor, use of the insulin-like growth factor/cation-independent mannose-6-phosphate receptor (IGF-II/CI-MPR) has been proposed for delivery of deficient lysozymes to cells (Kornfeld, S., 1987 Biochem Soc Trans 18:367-374). The IGF-II/CI-MPR receptor is present on the surface of many mammalian cell types and thus provides a means by which to target proteins containing the receptor ligand (e.g., IGFII or mannose-6 phosphate) to a wide variety of cells and tissues, including the central nervous system. However, despite some knowledge of how to target missing lysosomal enzymes to appropriate tissues, there are still no effective therapies for many lysosomal storage disorders (e.g., Sanfilippo syndrome, Farber's disease, and the like). Thus, there remains a need in the art for compositions, particularly compositions that can be administered parenterally, and methods useful for directing agents to the necessary tissues to treat diseases (e.g., lysosomal storage diseases).